This invention relates to N-[2-amino-4-substituted-[[(pyrrolo or pyrido)[2,3-d]pyrimidinyl]-alkyl]benzoyl]-L-glutamic acid compounds, certain of their reduced forms, intermediates for their synthesis, pharmaceutical formulations containing those compounds, and their use as antineoplastic agents.
Folic acid is a coenzyme in various enzymatic reactions such as those in the biosynthesis of nucleic acid and the metabolism of amino acids and peptides. Folate cofactors which are derived from folic acid are essential to biosynthesis of nucleic acids in two pathway--the purine synthetic pathway and the thymidine synthetic pathway. Generally, folic acid is required to be transformed into its activated coenzyme form by a two step reduction before it becomes biologically active. Compounds such as amethopterin are known to inhibit the second reduction, from dihydrofolic acid to tetrahydrofolic acid, by coupling strongly with the required enzyme, dihydrofolic reducatase. Such inhibitors are continuously being developed as antitumor drugs because they may disturb the DNA synthesis and cause cell death by preventing the regeneration of biologically active tetrahydrofolates.
Various derivatives of folic acid and aminopterin have been synthesized and tested as folic acid metabolite inhibitors. Among these are various "deaza" compounds in which a methylene or methylidene group occupies a position in the molecule normally occupied by an imino or nitrilo group, respectively. These derivatives have varying degrees of activity as metabolite inhibitors. A tetrahydroaminopterin antitumor agent 5,10-dideaza-5,6,7,8-tetrahydroaminopterin (DDATHF) inhibits glycinamide ribonucleotide transformylase, an enzyme required in the initial stage of purine biosynthesis; J. Med. Chem., 28, 914 (1985).
In European Patent Application EP 0 334 636, certain pyrrolopyrimidine derivatives are disclosed as having antitumor effects in mammals. In U.S. Pat. No. 4,684,653 certain pyrido[2,3-d]pyrimidine derivatives are disclosed as antineoplastic agents. The compounds of the present invention are distinguished from the above two references at least by virtue of their 4-position substituent.